Periodic Reporting for period 4 - NEUROMITO (Elucidating Neuronal Susceptibility to Mitochondrial Disease)
Período documentado: 2019-11-01 hasta 2020-04-30
Mitochondria generate most of the energy cells require to function. Deficits in the mitochondrial energy-generating machinery affect 1:5,000 children and cause progressive, debilitating, and usually fatal pathologies collectively known as primary mitochondrial disease. To date, there is no cure for mitochondrial disease and existing treatments are highly ineffective and mostly palliative. High-energy-requiring cells, such as neurons, are especially affected in mitochondrial disease. However, not all neuronal populations are equally affected and the molecular alterations leading to this vulnerability are unknown. To improve on current knowledge on mitochondrial disease and to provide better therapeutic targets, Neuromito focuses on developing new tools that will allow to dissect the mitochondrial function with unprecedented resolution. These tools will help identifying novel therapeutic targets that will lead to effective treatments for mitochondrial disease. Neuromito is divided in three research lines: identifying and characterizing the neuronal circuits affected by mitochondrial disease, determine the molecular alterations in such neurons, and identifying molecular targets with therapeutic potential.
As such, this project has been able to identify:
* The contribution of brainstem glutamatergic neurons in the regulation of autonomic responses, with clinical relevance.
* The existence of different molecular pathways leading to neurodegeneration after mitochondrial dysfunction, which are dependent on the cellular context.
* Several potential new therapies for mitochondrial disease based on the altered pathways, some of which are currently being developed.
* Highly-applicable, novel technologies, with both academic and commercial interest.
As such, this project has been able to identify:
* The contribution of brainstem glutamatergic neurons in the regulation of autonomic responses, with clinical relevance.
* The existence of different molecular pathways leading to neurodegeneration after mitochondrial dysfunction, which are dependent on the cellular context.
* Several potential new therapies for mitochondrial disease based on the altered pathways, some of which are currently being developed.
* Highly-applicable, novel technologies, with both academic and commercial interest.
In this project we have successfully identified and characterized the affected neuronal populations in a model of mitochondrial disease. Furthermore, we have already developed and validated several molecular biology tools to allow the characterization of mitochondrial function in specific cell types. Using these tools, we have been able to provide a comprehensive description of the molecular and elecrophysiological alterations in different neuronal populations in response to mitochondrial dysfunction.
Ongoing research is aimed at implementing this novel technology in a model of mitochondrial disease to uncover the molecular underpinnings causing neuronal death in this pathology, to elucidate the biological consequences of each of these neuronal populations in the development and progression of the disease and to identify molecular pathways that can provide novel therapeutical targets.